Impaired glutamate homeostasis in the nucleus accumbens in human cocaine addiction

Abstract

Cocaine addiction is characterized by overwhelming craving for the substance, which drives its escalating use despite adverse consequences. Animal models suggest a disrupted glutamate homeostasis in the nucleus accumbens to underlie addiction-like behaviour. After chronic administration of cocaine, rodents show decreased levels of accumbal glutamate, whereas drug-seeking reinstatement is associated with enhanced glutamatergic transmission. However, due to technical obstacles, the role of disturbed glutamate homeostasis for cocaine addiction in humans remains only partially understood, and accordingly, no approved pharmacotherapy exists. Here, we applied a tailored proton magnetic resonance spectroscopy protocol that allows glutamate quantification within the human nucleus accumbens. We found significantly reduced basal glutamate concentrations in the nucleus accumbens in cocaine-addicted (N = 26) compared to healthy individuals (N = 30), and increased glutamate levels during cue-induced craving in cocaine-addicted individuals compared to baseline. These glutamatergic alterations, however, could not be significantly modulated by a short-term challenge of N-acetylcysteine (2400 mg/day on two days). Taken together, our findings reveal a disturbed accumbal glutamate homeostasis as a key neurometabolic feature of cocaine addiction also in humans. Therefore, we suggest the glutamatergic system as a promising target for the development of novel pharmacotherapies, and in addition, as a potential biomarker for a personalised medicine approach in addiction.

Reduced Glutamate Turnover in the Putamen Is Linked With Automatic Habits in Human Cocaine Addiction

“…The significant reduction in glutamate concentration in the putamen and the low glutamate turnover in patients with CUD is in keeping with previously published findings in CUD, suggesting a substantial downregulation of glutamate neurotransmission, including widespread reduction in glutamate receptors (29,76,77) and low glutamate concentrations (27,30). To the best of our knowledge, our study is the first to show in humans a link between abnormal glutamate turnover and increased automatic habits.…”

“…There appears to be conflicting evidence on changes of these neurotransmitters in cocaine-addicted humans. While some studies suggest either increased (26) or decreased (27,28) cortical levels, subcortical levels of glutamate were either unchanged (29) or reduced (30). These inconsistencies may result from interactions between dopamine and glutamate (31), possibly reflecting individual differences in striatal dopamine depletion due to varying degrees of cocaine use in the samples studied (31).…”

N-acetylcysteine in substance use disorder: a lesson from preclinical and clinical research

“…Furthermore, in rodents drug-seeking reinstatement raises extracellular accumbal glutamate levels [14]. In line with animal research, clinical data using tailored proton magnetic resonance spectroscopy demonstrated that people with cocaine use disorder have reduced basal glutamate concentrations and increased glutamate levels in the nucleus accumbens during cueinduced craving [15]. This finding is supported by another proton magnetic resonance spectroscopy trial involving the dorsal anterior cingulate cortex, where glutamate levels were significantly higher in cocaine-dependent patients compared with healthy controls [16].…”

Neurochemical substrates linked to impulsive and compulsive phenotypes in addiction: A preclinical perspective

“…This report and others (Wang et al, 2010) highlight the important role of NMDAR subunit composition on glutamatergic signalling and reward seeking. In humans, perturbations in glutamate concentration are reported in the NAcb (Engeli et al, 2020) and caudate putamen (Ersche et al, 2020) of substance dependent individuals.…”